A. Tapp

Olanzapine-Induced Weight Gain and Increased Visceral Adiposity is Blocked by Melatonin Replacement Therapy in Rats

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n=11/group) of female rats (240–250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all p<0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.

Organizational and unit factors contributing to reduction in the use of seclusion and restraint procedures on an acute psychiatric inpatient unit.

ObjectiveThe use of seclusion or restraint (S/R) as an emergency medical intervention to assist patients in regaining behavioral control continues to be an area of interest and concern for the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO), consistent with the ongoing concerns in the medical, patient advocate, legislative and legal communities. This study examined unit characteristics and the use of S/R in a VA facility with a secured, acute mental health unit before and after the promulgation of the JCAHO 2000 standards for utilization of S/R for behavioral health reasons.MethodsVariables examined include patient acuity, patient census, number of admits, number of discharges, length of stay, number of nursing staff on duty, critical incidents and S/R hours per month.ResultsResults indicated S/R use began showing a notable decrease corresponding to the time that senior unit management began discussions of the new JCAHO standards. These reductions maintained statistical significance even after controlling for changes in unit environmental variables.

Open trial of injectable risperidone for methamphetamine dependence.

We tested acceptability and tolerability of long-acting injectable risperidone for methamphetamine (MA) dependence in an open trial with the hypothesis that participants would reduce MA use. Participants were also evaluated for changes in neurocognitive function and psychiatric symptomology. Participants with MA dependence (n = 34) entered a 7-day open-label run-in with oral risperidone. Participants who tolerated oral risperidone (n = 22) were begun on long-acting injectable risperidone 25 mg intramuscular medication with subsequent injections q 2 weeks to a total of 4 injections. Participants remained on oral risperidone during the first 3 weeks after initial injection. Participants were offered 8 weekly individual sessions of relapse prevention counseling. At baseline, participants reported using MA an average of 4.1 days per week (SD = 1.9). Estimated mean days of MA use per week while on injections was 1.0 (95% confidence interval = 0.6–1.4), with days of use decreasing significantly from baseline through week 8 (β = −0.27; 95% confidence interval: − 0.38–−0.16; P < 0.001). Mean week 6 risperidone + 9-OH risperidone plasma levels for participants abstinent from MA from weeks 5 to 8 (n = 7, 63.6%) were 18.8 ng/mL (SD = 6.6) compared with 12.3 (SD = 4.0) for those not abstinent (n = 4; P = 0.075). No serious adverse events occurred. Verbal memory improved at week 4 compared with baseline (P < 0.05). Participation in this trial of injectable risperidone was associated with reductions in MA use as well as some positive benefits on verbal memory. However, these results are limited by the use of an open trial design with a high dropout rate. Risperidone deserves further study in controlled trials as a pharmacotherapy for MA dependence.

Quetiapine for the treatment of cocaine use disorder.

BACKGROUND Cocaine addiction continues to be a significant healthcare issue, yet there are no FDA approved medications for the treatment of cocaine use disorder within the United States. METHODS This 12-week, prospective, double-blind, randomized, placebo-controlled study examined the effectiveness of quetiapine (Seroquel XR™) versus matched placebo for the treatment of DSM-IV cocaine dependence in non-psychotic individuals. Subjects randomized to quetiapine (N = 29) were titrated up to a target dose of 400mg/day of quetiapine, while those in the placebo arm (N = 31) were given a matched placebo. All subjects had weekly clinic visits and a cognitive-behavioral therapy group session. Outcome measures included self-report of cocaine use and money spent on cocaine as well as urine drug screens (UDS). RESULTS The drop-out rate was substantial at 68%. Logistic regression analysis did not find significant differences between groups in predicting end-of trial abstinence, defined as three consecutive weekly negative UDS (13.7% in the quetiapine group versus 12.9% in the placebo group; p = .92). Based upon a repeated measures analysis of variance, subjects in this study, as a whole, demonstrated reductions in their self-reported use of cocaine, self-reported money spent on cocaine, and number of days per week using cocaine. However, the quetiapine group did not differ significantly from the placebo group. CONCLUSIONS This study did not find group differences between the quetiapine and placebo arms, suggesting that quetiapine is not an efficacious treatment for DSM-IV cocaine dependence.

EPA-0982 – Olanzapine, correction of melatonin suppression, and metabolic indices

Objective Animal research suggests that weight gain may be caused by olanzapine-induced melatonin suppression. We conducted a pilot study of psychiatric patients treated with olanzapine to examine if melatonin was suppressed and if so the dose needed to replace this deficit. The relationship between melatonin and metabolic indices was also examined. Method Ten patients with schizophrenia (N=3), schizoaffective disorder (N=3), or bipolar disorder (N=4) completed the study. All patients were male, average age 50.6 years. Patients were treated with olanzapine for 5 weeks, then randomized to either 0.3mg (N=4) or 3mg (N=6) of melatonin supplementation in addition to the olanzapine for another 6 weeks. We obtained baseline, week-6, and week-12 measures of the major metabolite of melatonin in the urine, 6-Sulfatoxymelatonin (aMT6s) adjusted for creatinine excretion. We measures weekly weight, glycemia, cholesterol, and triglycerides. Result Olanzapine treatment was associated with a trend toward decreases in melatonin from baseline to week-6 (p=.14). Analysis of a subsample of patients diagnosed with schizoaffective or bipolar disorder showed significant decreases from baseline to week-6 (p=.02). Both supplementation with melatonin by 0.3mg and 3mg increased urinary melatonin levels from week-6 to week-12 (p=.12 and p=.02 respectively). Total cholesterol increased initially but demonstrated a trend for decrease when melatonin was supplemented (p=.10). Conclusion Olanzapine appears to be related to melatonin suppression. Melatonin supplementation reverses this suppression and may have the potential to reverse metabolic effects associated with olanzapine. Further studies are needed to examine the metabolic effects of olanzapine with melatonin.